This application is submitted in response to an RFA-OD-09-004 entitled "Recovery Act Limited Competition for NIH Grants: Research and Research Infrastructure "Grand Opportunities" (RC2)" and addresses the NIDCR Area of Scientific Priority "Genome-wide Studies in Craniofacial, Dental, and Oral Conditions". Periodontitis is a prevalent, complex dental disease characterized by loss of periodontal attachment and oral bone. Although periodontitis has a high genetic determination, specific genes underlying susceptibility to the disease are still largely unknown. Genome-wide association (GWA) analyses represent a powerful strategy for dissection of genetic etiologies of common human diseases, but a well-designed, powerful GWA study (GWAS) has not been performed on periodontitis. Our general hypothesis is that risk genes for periodontitis can be detected with a powerful GWAS. The GOAL here is to identify such genes with GWA analyses followed by validation in an independent population. Potential non- genetic factors and their interactions with potential periodontitis genes will also be assessed. Under this goal, we will achieve the following two Specific Aims: Aim 1: To perform a powerful and efficient GWAS for genes underlying risk to periodontitis, using the latest GWA array for SNPs and copy number variants (CNVs), the Affymetrix Genome-wide Human SNP Array 6.0, in 2,001 unrelated Caucasians, including 1,000 subjects having severe periodontitis (cases) vs. 1,001 periodontally healthy controls. The subjects are selected from 3 NIH-supported, population-based periodontal studies implemented at the State University of New York at Buffalo. Aim 2: To replicate/validate the top 0.5% (~5,000) most significant SNPs/CNVs identified in Aim 1 in an independent cohort selected from Dental ARIC population, which contains ~2,300 unrelated Caucasians, including ~700 severe periodontitis cases vs. ~1,600 periodontally healthy controls. Joint analysis of data from Aims 1 and 2 will also be performed to substantiate genes/markers associated with periodontitis with much enhanced power. All these subjects have been genotyped with Affymetrix SNP Array 6.0, the same array to be used in our GWAS in Aim 1, which will greatly facilitate our proposed replication analyses. Identification of the risk genes for periodontitis is important for 1) gaining novel insights into the fundamental molecular mechanisms underlying this complex disease;2) discovering new pathways and targets for therapeutic cures;and 3) identifying subjects genetically susceptible to periodontitis so that early and effective preventions /interventions can be achieved by targeting to and basing on an individual's specific genotypes. This project is built upon a multi-disciplinary team with 1) extensive experience in GWAS of human complex diseases/traits, evidenced by our recently published 9 GWAS papers;and 2) broad experience in research of periodontal disease, witnessed by Dr. Genco's group's long and pioneering investigations on periodontitis. PUBLIC HEALTH RELEVANCE: This project aims to identify genes underlying risk of periodontitis, a prevalent dental disease of significant public health burden in the US. The findings from this project will contribute to effective treatment and early prevention of the disease.